P962: CHANGE IN SOLUBLE BCMA LEVEL MAY BE A SURROGATE MARKER OF EARLY RESPONSE TO THERAPY IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM): PRELIMINARY RESULTS FROM A PHASE I STUDY OF CEVOSTAMAB
Authors: R. Nakamura, R. Hendricks, R. Dokhaei, M. Susilo, D. Wilson, S. Trudel, A. Cohen, S. J. Harrison, A. Krishnan, R. Fonseca, J. I. Adamkewicz, M. Li, C. Wong, J. Cooper, T. Sumiyoshi
Journal: HemaSphere (2022)

Background: Cevostamab is an FcRH5xCD3 bispecific antibody that facilitates T-cell directed killing of myeloma cells, and has shown promising activity and manageable safety in a Phase I study in patients (pts) with RRMM (NCT03275103; Trudel et al. ASH 2021). B-cell maturation antigen (BCMA) is a membrane-bound protein that is expressed preferentially by malignant plasma cells and has become an important therapeutic target in MM. Shedding of membrane-bound BCMA, mediated by γ-secretase, gives rise to the soluble form of BCMA (sBCMA) which is often present at elevated levels in pts with MM. Normalization of sBCMA may be a predictor of response to therapy, which may be independent of treatment and target. Aims: To evaluate sBCMA as a biomarker of early response in pts enrolled in the single step-up dosing cohorts of the cevostamab Phase I study. Methods: Plasma samples were collected at baseline and at Cycle (C) 1 Day (D) 1 (pre-infusion and end of infusion [EOI]), C1D2, C1D4, C1D8 (pre-infusion and EOI), C1D9, C1D11, and C2D1 (pre-infusion and EOI). sBCMA levels were quantified using hybrid immunoaffinity capture with LC-MS/MS. Pts were stratified by refractory status, prior therapy, prior transplant, cytogenetic risk and response (responder [≥PR] or non-responder [<PR]), and samples from each category were grouped for analysis. Associations between baseline sBCMA levels and baseline patient characteristics or response to treatment were evaluated using an unpaired 2-sample Wilcoxon test (significance level: p≤0.05). The relationship between sBCMA dynamics (percent change in sBCMA level from baseline to C2D1 EOI) and best response was evaluated using logistic linear regression. All pts provided informed consent. Results: At cut-off (January 7, 2022), 97/103 pts in the single step-up cohorts were biomarker evaluable. No clear differences in baseline sBCMA levels were observed in pts stratified by refractory status, prior transplant, or prior anti-CD38 or anti-BCMA therapy. Analysis of a subset of pts with cytogenetic data showed a trend towards lower baseline sBCMA levels in the standard-risk group (n=18) vs the high-risk group (n=42; p=0.032). In the active dose cohorts (3.6/20mg+; n=77), baseline sBCMA levels were comparable between responders and non-responders. However, baseline sBCMA levels were lower in pts achieving a VGPR or better vs those achieving a PR or no response (median: 47.7ng/mL vs 120.5ng/mL; p=0.037). At C2D1 EOI, most responders had a reduction in sBCMA relative to baseline, with the pts who achieved sCR having the greatest decrease (median: –92.10%). In comparison, an increase in sBCMA was observed in non-responders at C2D1 EOI, with the pts who had PD having the greatest increase (median: 93.14%). The extent of reduction in sBCMA from baseline to C2D1 EOI was significantly correlated with best overall response rate (PR or better) (p=1.8x10–5). Summary/Conclusion: In this study, baseline sBCMA was not associated with refractory status, prior transplant or treatment in pts with RRMM. Patients with standard-risk cytogenetics had lower baseline sBCMA levels vs those with high-risk cytogenetics. The kinetics of sBCMA change from baseline to C2D1 EOI corresponded with response to cevostamab, with greater reductions increasing the probability of best response. These early data suggest that sBCMA dynamics may be a potential tool for early disease monitoring and identification of response in RRMM. Updated data will be presented.